U.S. Pat. Nos. 6,448,267, 6,455,542 and 6,759,430 disclose, inter alia, 1-pyrrolidinyloxy, 1-piperidinyloxy and 1-azepanyloxy derivatives comprising a nitric oxide donor and a O2− scavenger, capable of acting as sources of nitric oxide and as ROS degradation catalysts, their preparation, and their use in the treatment of various conditions associated with oxidative stress or endothelial dysfunction such as diabetes mellitus and cardiovascular diseases.
International Publication No. WO 2012/093383 discloses methods and compositions for treatment of sepsis and conditions associated therewith using the compounds disclosed in U.S. Pat. Nos. 6,448,267, 6,455,542 and 6,759,430; International Publication No. WO 2011/092690 discloses methods and compositions for prevention, treatment, or management of pulmonary arterial hypertension (PAH) using those compounds; International Publication No. WO 2013/005216 discloses methods and compositions for prevention and treatment of renal ischemia-reperfusion injury; and International Publication No. WO 2013/190497 discloses methods and compositions for treatment of Cl2 inhalational lung injury (CILI). The entire contents of each and all these patents and patent publications being herewith incorporated by reference in their entirety as if fully disclosed herein.
As shown in International Publication No. WO 2013/005216, the compounds disclosed in U.S. Pat. Nos. 6,448,267, 6,455,542 and 6,759,430, in particular 3-nitratomethyl-2,2,5,5-tetramethylpyrrolidinyloxy, herein identified R-100, that is specifically exemplified in the aforesaid International publications for treatment of sepsis, PAH, renal ischemia-reperfusion injury, and CILI, are highly insoluble in water but are soluble in certain organic solvents such as dimethyl sulfoxide (DMSO) or alternatively, when formulated as inclusion complexes with hydroxyalkylcyclodextrin such as hydroxypropylcyclodextrin (HPCD). The inclusion of such organic solvents in pharmaceutical compositions is potentially toxic and is thus preferably avoided. HPCD is relatively well tolerated but must be admixed with R-100 in a ratio of >20:1 (HPCD:R-100) in order to fully dissolve said compound. The upper limit of safety for clinical administration of HPCD is unknown, but the greatest amount approved for use in humans via an intravenous route is a daily quantity of 7 grams. Given the minimum usable ratio of 20:1 for the dissolution of R-100 and HPCD, and the limit of 7 grams of HPCD per day, the maximal amount of R-100 delivered in such an intravenous formulation would be 350 mg daily.